A Practical Approach to Risk Stratification for PMF: from IPSS to DIPSS-plus
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1 A Practical Approach to Risk Stratification for PMF: from IPSS to DIPSS-plus Francisco Cervantes Hematology Department, Hospital Clínic, Barcelona, Spain Lisbon, May 2012 Primary Myelofibrosis: Age Distribution (n= 180) Median: 64 years (17-89) Years
2 Clinical Manifestations and Laboratory Features of Myelofibrosis Symptoms Physical findings Hematologic abnormalities Bone marrow features Molecular abnormalities - Anemic symp. - Splenomegaly - Constitutional Splenomegaly (+ hepatomegaly) Anemia Leukocytosis Leukopenia Thrombocytosis Thrombocytopenia Abnormal megak. Cytogenetic abn. Fibrosis Osteosclerosis JAK2 V617F C-MPL Relative Survival in PMF Cervantes et al., Blood 2009; 113:
3 Survival in PMF No. patients: 1,054 Median Srv (95% CI): 69 (61-76) Deaths: 517 (49 %) Cervantes et al., Blood 2009; 113: Survival of PMF Patients < 55 years (n= 121) Median: 10.6 years Probability Years Cervantes et al., Br J Haematol 1998; 102:884-90
4 Causes of Death in PMF 13% 4% 4% 5% 10% 14% 19% 31% Cervantes et al., Blood 2009;113: Prognostic Scoring Systems of PMF Author (year) Prognostic factors Risk groups Median srv * Visani (1990) Hb < 10 g/dl Blood myeloid precursors > 10% 3 81, 39, 31 Dupriez (1996) Cervantes (1997) Hb < 10 g/dl WBC < 4 or > 30 x10 9 /L Hb < 10 g/dl Constitutional symptoms Blood blasts > 1% 3 93, 26, , 21 Reilly (1997) Tefferi (2007) Hb < 10 g/dl Age > 68 yrs 2 108, 16 Abnormal karyotype Hb < 10 g/dl WBC < 4 or > 30 x10 9 /L 3 134, 50, 29 Platelets < 100 x10 9 /L Monocytes > 1 x10 9 /L Studies not including prefibrotic PMF; * months
5 Dupriez s Prognostic Score Adverse factors Hb < 10 g/dl WBC < 4 or > 30 x 10 9 /L Prognostic groups Low risk: 0 factors Intermediate risk: 1 factor High risk: 2 factors Median survival 93 months 26 months 13 months Dupriez et al., Blood 1996; 88: IPSS: Risk Classification of PMF at Presentation Prognostic factors Age > 65 years.9 Constitutional symptoms.8.7 Hb < 10 g/dl.6 Leukocytes > 25 x 10 9 /L Blood blasts > 1% Risk groups Low 0 Intermediate-1 1 Intermediate-2 2 High > 3 Probability Survival by PMF-PS Months 95% CI 95% CI 95% CI 95% CI PMF-PS = 0 PMF-PS = 1 PMF-PS = 2 PMF-PS = 3 Cervantes et al., Blood 2009;113:
6 PMF- IPSS Risk Groups Risk No. Median Srv Patient % Group factors (95% CI) % Deaths Low 0 22 % 135 ( ) 32 % Interm % 95 (79-114) 50 % Interm % 48 (43-59) 71 % High 3 21 % 27 (23-31) 73 % Cervantes et al., Blood 2009; 113: IPSS of PMF: Relative Survival by Risk Group Low Intermediate Probability Intermediate 2 High Observed Population Relative Years Cervantes et al., Blood 2009; 113:
7 Dynamic IPSS (DIPSS) of PMF: Weight of Variables and Risk Groups Passamonti et al., Blood 2010; 115: DIPSS: Time of Appearance of Risk Factors Passamonti et al., Blood 2010; 115:
8 DIPSS of PMF: Survival by Risk Group Overall Series Passamonti et al., Blood 2010; 115: DIPSS in Patients < 65 years: Weight of Variables and Risk Groups Passamonti et al., Blood 2010; 115:
9 Survival by DIPSS Risk Groups for Patients < 65 years Passamonti et al., Blood 2010; 115: Cytogenetic Abnormalities in PMF More frequent abnormalities Others Trisomy 9 del 20q del 7 / 7q- del 13q del 5 / 5q- t (1;7) Trisomy 8 del 12p Trisomy 1q del 17 / iso 17q Rearr. 11q23 Inv (3) t (1;6)
10 Karyotype and Prognosis in PMF Favorable: 13q-, 20q-, +9 Normal diploid Unfavorable: Abnormal 5, 7 or 17 Complex Tam et al., Blood 2009 Karyotype and Prognosis in PMF Favorable: 13q-, 20q-, +9 Unfavorable: Complex, +8 Normal diploid Others Hussein et al., Blood 2010
11 DIPSS-Plus for Primary Myelofibrosis *** Complex karyotype or +8, -5/-5q-, -7/-7q, i(17q), 12p-, inv(3), 11q23 rearr. Gangat et al., JCO 2011; 29: DIPSS-Plus for Primary Myelofibrosis Gangat et al., JCO 2011; 29:
12 Summary of Current Prognostic Models for PMF Cervantes et al., Blood 2009; 113: Passamonti et al., Blood 2010; 115: Gangat et al., JCO 2011; 29: Very High Risk PMF Patients: > 80% Mortality at 2 Years Very High risk variables monosomal karyotype inv(3)/i(17q) or any 2 of the following: PB blasts >9% WBC >40x10 9/ L other unfavorable karyotype Int 1 (11%) Low (3%) High (53%) Int 2 (26%) Very High (82%) Tefferi et al., Blood 2011; 118:4595 8
13 Mutation JAK2 V617F in the MPNs V617F FERM SH2 JH2 JH1 Aminoterminal Carboxyterminal Frequency of the JAK2 mutation PV ET PMF 90-95% 50-60% 60% Prognostic Value of the JAK2 Mutation in PMF Author No. of Prognostic (year) patients influence Tefferi (2005) 157 No Campbell (2006) 152 Yes Barosi (2007) 174 Yes * Cervantes (2009) 345 No Guglielmelli (2009) 186 Yes ** * Higher leukemic transformation rate; ** shorter survival for lower burden
14 Other Mutations in PMF Gene Chromosome location Frequency TET2 CBL ASXL1 IDH IKZF1 EZH2 4q 11q 20q 2q 7p 7q 20% 6% 13-23% 1-4% 0-4% 6-13% Tefferi A,. Leukemia 2010; Guglielmelli et al., 2011 Newer Mutations and Prognosis of PMF: EZH2 Mutations of EZH2 (catalytic component of Polycomb Repressive Complex 2) are found in 6% of PMF subjects Overall Survival EZH2 WT EZH2 mut P< kemia free Survival Leu EZH2 WT EZH2 mut P= In multivariate analysis, EZH2 mutated status was an IPSS independent variable significantly associated with reduced OS (P=0.016) Guglielmelli et al., Blood 2011; 118;19:
15 Newer Mutations and Prognosis of PMF: IDH Tefferi et al., Leukemia 2012; 26: Treatment Options for Myelofibrosis Wait & see Conventional treatment Investigational drugs Allo-HSCT
16 Factors Driving Therapy Choice in Myelofibrosis Prognostic Group Symptom Type & Burden Poor Other Prioritize curative options (HSCT) or investigational drugs Therapy adjusted to symptoms Proposed Algorithm for PMF Treatment Low risk Intermediate-1 risk Intermediate-2 risk High risk Wait & see Wait & see or Symptomatic treatment * Conventional or Investigational Drugs / Allo-HSCT ** Allo-HSCT or Investigational drugs * Check cytogenetics & transfusion dependency * Poor cytogenetics Transfusion dependency, No response to treatment
17 Thanks
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